Time to harmonise common laboratory test profiles

We read with interest the recent article by the Association for Clinical Biochemistry (ACP)’s Clinical Practice Section entitled ‘Time to harmonise common laboratory test profiles’[1]. Whilst we are in favour of these attempts to rationalise simple blood test profiles, in our opinion the draft proposals do not go far enough and will add little in terms of value to the existing ‘liver profile’and its clinical application.

As the authors indicate in their article, despite a popular label of ‘liver function tests’, traditional panels aren’t useful in assessing the degree of liver injury nor do they accurately predict important clinical outcomes. This is evident from the fact that none of the validated prognostic models used in clinical decision making such as Child-Pugh score, King’s College Criteria, Model for End-stage Liver Disease (MELD) or UK End Stage Liver Disease (UKELD) include liver enzymes as their components.

Persistent dogma means that the higher a patient’s liver enzymes, the more likely that further investigations are carried out; yet the histological spectrum found in non-alcoholic fatty liver disease (NAFLD) patients with normal and elevated alanine aminotransferase levels are identical[2]. Moreover, in a recent large general practice study based in Birmingham[3], 1118 patients with raised liver enzymes were thoroughly investigated, and a liver related cause could only be identified in 55% of patients. Continued reliance on alanine transaminase (ALT) elevation has contributed to both over-referral; in one study, 33% of secondary care referrals from general practitioners on investigation had simple steatosis only[4], as well as under-referral; nearly 50% of those who required investigations in primary care were neither referred nor adequately investigated in another study from the same region[5]. The changes proposed by the ACP may achieve uniformity, but do little to enhance the clinical utility of liver enzymes.

After decades of use and misuse of liver enzymes in clinical practice, it is time that we critically appraise their application in the current context. In contrast with a lack of correlation of elevated liver enzymes with the degree of liver injury or loss of function, the aspartate to alanine aminotransferase (AST/ALT) ratio is validated as a marker of severity in chronic liver diseases secondary to alcohol[6], NAFLD [7], and primary sclerosing cholangitis[8]. This ratio reflects the structural changes (the degree of liver fibrosis) within the liver which precede any deterioration in liver function. Using a cut-off value of 0.8 for the AST/ ALT ratio, and in combination with established risk factors for chronic liver disease such as presence of diabetes and obesity (the BARD score), a negative predictive value of greater than 95%, to rule out significant liver scarring in NAFLD can be achieved[7, 9]. Routine reporting of AST/ALT ratio would improve the clinical utility of the liver profile without added cost.

With a striking rise in the burden of chronic liver disease in the United Kingdom, it is time to introduce AST/ ALT ratio as an evidence based non-invasive biomarker that could reduce unnecessary referrals without missing significant disease.

References:

[1] Smellie W. Time to harmonise common laboratory test profiles. BMJ 2012;344:e1169.
[2] Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37:1286-1292.
[3] Armstrong MJ, Houlihan DD, Bentham L, Shaw JC, Cramb R, Olliff S, et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J Hepatol 2012;56:234-240.
[4] Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. Journal of Hepatology 2001;35:195-199.
[5] Sherwood P, Lyburn I, Brown S, Ryder S. How are abnormal results for liver function tests dealt with in primary care? Audit of yield and impact. BMJ 2001;322:276-278.
[6] Nyblom H, Berggren U, Balldin J, Olsson R. High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol Alcoholism 2004;39:336-339.
[7] McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59:1265-1269.
[8] Nyblom H, Nordlinder H, Olsson R. High aspartate to alanine aminotransferase ratio is an indicator of cirrhosis and poor outcome in patients with primary sclerosing cholangitis. Liver Int 2007;27:694-699.
[9] Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008;57:1441-1447